title: Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments.
abstract: The present study investigated prediction of the overall renal tubular secretion and hepatic clearances of anionic drugs based on in vitro transport studies. The saturable uptake of eight drugs, most of which were OAT3 substrates (rosuvastatin, pravastatin, pitavastatin, valsartan, olmesartan, trichlormethiazide, p-aminohippurate, and benzylpenicillin) by freshly prepared human kidney slices underestimated the overall intrinsic clearance of the tubular secretion; therefore, a scaling factor of 10 was required for in vitro-in vivo extrapolation. We examined the effect of gemfibrozil and its metabolites, gemfibrozil glucuronide and the carboxylic metabolite, gemfibrozil M3, on pravastatin uptake by human kidney slices. The inhibition study using human kidney slices suggests that OAT3 plays a predominant role in the renal uptake of pravastatin. Comparison of unbound concentrations and K(i) values (1.5, 9.1, and 4.0 μM, for gemfibrozil, gemfibrozil glucuronide, and gemfibrozil M3, respectively) suggests that the mechanism of the interaction is due mainly to inhibition by gemfibrozil and gemfibrozil glucuronide. Furthermore, extrapolation of saturable uptake by cryopreserved human hepatocytes predicts clearance comparable with the observed hepatic clearance although fluvastatin and rosuvastatin required a scaling factor of 11 and 6.9, respectively. This study suggests that in vitro uptake assays using human kidney slices and hepatocytes provide a good prediction of the overall tubular secretion and hepatic clearances of anionic drugs and renal drug-drug interactions. It is also recommended that in vitro-in vivo extrapolation be performed in animals to obtain more reliable prediction.
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Tomoko
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Debori
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Tsunenori
authors.initials: T
authors.lastname: Kondo
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Shigeru
authors.initials: S
authors.lastname: Horita
authors.forename: Brian W
authors.initials: BW
authors.lastname: Ogilvie
authors.forename: Andrew
authors.initials: A
authors.lastname: Parkinson
authors.forename: Zhuohan
authors.initials: Z
authors.lastname: Hu
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000838:Anions; D002478:Cells, Cultured; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007684:Kidney Tubules / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis / Q000502:physiology*; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011237:Predictive Value of Tests; D013379:Substrate Specificity
chemical_list: D000838:Anions; D029362:Organic Anion Transporters, Sodium-Independent; D004364:Pharmaceutical Preparations; C114338:organic anion transport protein 3